Process for the preparation of 4-{4[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide, its salts and monohydrate

ABSTRACT

The present invention relates to a process for preparing 4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide, its salts and monohydrate.

The present invention relates to a process for preparing4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide,its salts and monohydrate.

4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamideis mentioned in WO 05/009961 and corresponds to the compound of theformula (I):

The monohydrate of the compound of formula (I) is mentioned in WO08/043446. Furthermore salts of the compound of formula (I) such as itshydrochloride, mesylate and phenylsulfonate are mentioned in WO05/009961 and can be formed by treating the compound of the formula (I)with the corresponding acid. The compound of formula (I) is describedfor treating hyper-proliferative disorders such as cancers, tumors,lymphomas, sarcomas and leukemias.

WO 05/009961 describes a process for preparing the compound of theformula (I), which is illustrated in the following scheme:

In the first step 4-amino-3-fluorophenol was treated with potassiumtert-butoxide and 4-chloro-N-methyl-2-pyridinecarboxamide was added inN,N-dimethylacetamide to form4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamide whichafter extraction was finally treated with4-chloro-3-(trifluoromethyl)phenyl isocyanate in toluene to form4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridine-2-carboxylicacid methylamide which is the compound of formula (I).

While the processes disclosed by the prior art are per se effective forpreparing the compound of the formula (I), its monohydrate,hydrochloride, mesylate and phenylsulfonate, factors such as purity,product yields, process efficiency, safety and economy are verysignificant for an industrial scale process of a pharmaceutical product.

It is an object of the present invention to provide a process forpreparing the compound of the formula (I), its salts and monohydrate inindustrial scale (kilogram to metric tons range) which satisfies thecriteria which apply in production and provides improvements in purity,environmental compatibility, industrial employability, safety aspectsand volume yield. Especially purity and safety aspects are to beconsidered for the preparation of pharmaceuticals. This object isachieved by the present invention.

The inventive preparation of the compound of the formula (I) is shown inthe following scheme:

Preparation of the Compound of the Formula (I), its Monohydrate orSalts:

The present invention comprises a process for preparing of the compoundof the formula (I)

its salt or monohydrate by treating the compound of the formula (IV)

which is 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide withthe compound of formula (V)

which is 4-chloro-3-trifluoromethyl-phenyl isocyanate in a reactionmixture and thereafter the solved compound of the formula (I) is treatedwith an acid to form a salt of the compound of the formula (I) whichprecipitates from the solution containing the solved compound of theformula (I), optionally the salt of the compound of the formula (I) isthen treated with an aqueous basic solution to precipitate themonohydrate of the compound of the formula (I), and optionally themonohydrate is dried under reduced pressure until the compound of theformula (I) is formed.

The salt of the compound of the formula (I) can be prepared by treatingthe compound of the formula (IV) with the compound of formula (V) in areaction mixture and thereafter the solved compound of the formula (I)is treated with an acid to form the salt of the compound of the formula(I) which precipitates from the solution containing the solved compoundof the formula (I).

The monohydrate of the compound of the formula (I) can be prepared bytreating the compound of the formula (IV) with the compound of formula(V) in a reaction mixture and thereafter the solved compound of theformula (I) is treated with an acid to form a salt of the compound ofthe formula (I) which precipitates from the solution containing thesolved compound of the formula (I), the salt of the compound of theformula (I) is then treated with an aqueous basic solution toprecipitate the monohydrate of the compound of the formula (I),preferably at a temperature of from 35° C. to 45° C., most preferablyfrom 38° C. to 42° C.

The compound of the formula (I) can be prepared by treating the compoundof the formula (IV) with the compound of formula (V) in a reactionmixture and thereafter the solved compound of the formula (I) is treatedwith an acid to form a salt of the compound of the formula (I) whichprecipitates from the solution containing the solved compound of theformula (I), the salt of the compound of the formula (I) is then treatedwith an aqueous basic solution to precipitate the monohydrate of thecompound of the formula (I) and the monohydrate is dried under reducedpressure until the compound of the formula (I) is formed, preferably ata temperature of 85° C. to 120° C., and preferably at a pressure ofbelow 30 mbar.

According to the processes described above the solution containing thesolved compound of the formula (I) and what from the salt of thecompound of the formula (I) precipitates can be preferably the reactionmixture or can be a separate solution containing the compound of theformula (I). The separate solution can be prepared after isolation ofthe compound of the formula (I) from the reaction mixture for example bystandard work-up procedures as described for example in WO 05/009961 andsolving the compound of the formula (I) in an suitable organic solvent.

In a preferred embodiment of the process for preparing of the compoundof the formula (I), its monohydrate or salt as described above the acidis generated in situ in the solution containing the solved compound ofthe formula (I) by adding to the reaction mixture a protic substance andan acid precursor.

In a more preferred embodiment of the process for preparing of thecompound of the formula (I), its monohydrate or salt the acid isgenerated in situ in the reaction mixture after the compound of theformula (I) is formed by adding to the reaction mixture an alcohol andan acid precursor.

In a most preferred embodiment of the process for preparing of thecompound of the formula (I), its monohydrate or salt the acid isgenerated in situ in the reaction mixture after the compound of theformula (I) is formed by adding to the reaction mixture an alcohol andan acylchloride, preferably acetylchloride.

In the process for preparing of the compound of the formula (I), itsmonohydrate or salt the reaction of the compound of the formula (IV)with the compound of the formula (V) is effected in an suitable organicsolvent, for example in tetrahydrofuran, at a temperature above 15° C.and below 70° C., preferably at a temperature of from 15° C. to 60° C.,more preferably from 15° C. to 50° C., most preferably at roomtemperature. Preference is given to initially charging the compound ofthe formula (IV) in a suitable organic solvent, for example intetrahydrofuran, and admixing within 30 to 300 minutes, preferablywithin 60 to 150 minutes, most preferably within 80 to 100 minutes thecompound of the formula (V), preferably dissolved or suspended in asuitable organic solvent, for example toluene, which can be different tothe first suitable organic solvent. After formation of the compound ofthe formula (I) an acid is added to the reaction mixture. Preferably theacid is generated in situ in the reaction mixture by adding a proticsubstance for example water and/or an alcohol, preferably an alcohol,and an acid precursor, preferably an acylchloride, within for example 5to 60 minutes, preferably within 10 to 30 minutes, in order to generatethe corresponding acid in situ. Preferably the protic substance is addedfirst. The salt of the compound of the formula (I) can be isolated byprecipitation.

In order to prepare the monohydrate of the compound of the formula (I)the salt of the compound of the formula (I) is further treated with anaqueous basic solution, preferably with a mixture of an organic solventand an aqueous basic solution. The monohydrate of the compound of theformula (I) can be isolated by precipitation, preferably at atemperature of from 35° C. to 45° C., most preferably from 38° C. to 42°C.

In order to prepare the compound of the formula (I) the monohydrate ofthe compound of the formula (I) is dried preferably at a temperature of85° C. to 120° C. and under reduced pressure, more preferably at apressure of below 30 mbar.

Suitable acids in the process for preparing of the compound of theformula (I), its monohydrate or salt include but are not limited tomineral acids, carboxylic acids and sulfonic acids, for examplehydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonicacid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonicacid, acetic acid, propionic acid, lactic acid, tartaric acid, malicacid, citric acid, fumaric acid, maleic acid and benzoic acid.Preference is given to hydrochloric acid, hydrobromic acid, sulfuricacid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonicacid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acidand naphthalenedisulfonic acid, more preferably to hydrochloric acid,benzenesulfonic acid, toluenesulfonic acid or methanesulfonic acid, mostpreferably to hydrochloric acid.

Salts of the compound of the formula (I) which are pharmaceuticallyacceptable salts include but are not limited to acid addition salts ofmineral acids, carboxylic acids and sulfonic acids, for example salts ofhydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonicacid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonicacid, acetic acid, propionic acid, lactic acid, tartaric acid, malicacid, citric acid, fumaric acid, maleic acid and benzoic acid.Preference is given to salts of hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, methanesulfonic acid,trifluoromethanesulfonic acid, ethanesulfonic acid, toluenesulfonicacid, benzenesulfonic acid and naphthalenedisulfonic acid, morepreferably to salts of hydrochloric acid, benzenesulfonic acid,toluenesulfonic acid or methanesulfonic acid, most preferably to thehydrochloric acid salt.

According to the present invention alcohols are organic substancescarrying at least one hydroxyl group. Alcohols include but are notlimited to methanol, ethanol, n-propanol, isopropanol, n-butanol,sec-butanol, isobutanol, n-pentanol, glycerol or a mixture thereof.Preferably methanol, ethanol and isopropanol are used as alcohols in thepresent process.

In order to prepare the acid in situ suitable acid precursors includebut are not limited to organic acid halogenides, preferablyacylhalegonides such as acylchlorides and acylbromides, more preferablyacetylchloride, a cetylbromide, propionylchloride or propionylbromide,most preferably acetylchloride.

Preference is given to a process described above wherein the acid isprepared in situ without water.

Suitable organic solvents in the process for preparing of the compoundof the formula (I), its monohydrate or salt include but are not limitedto tetrahydrofuran, toluene, ethyl acetate, dioxane, methyl tert-butylether, dimethoxyethane, dimethylsulfoxid, dimethylformamid,1-methyl-2-pyrrolidinone or mixtures of the mentioned solvents. Morepreferably tetrahydofuran, toluene and mixtures thereof are used.

Suitable aqueous basic solutions in the process for preparing of themonohydrate of the compound of the formula (I) include but are notlimited to aqueous solutions of alkali metal hydroxides, alkali earthmetal hydroxides, alkali metal alkoxides, alkali earth metal alkoxides,organic amines and ammonia, preferably sodium hydroxide and potassiumhydroxide, more preferably an aqueous solution of sodium hydroxide. Theaqueous basic solution can be mixed with an organic solvent such asacetone, ethyl acetate, tetrahydrofuran, preferably with acetone.

According to the present process potential side products, in particularanilinic side products such as the starting compounds4-amino-3-fluorophenol and the compound of the formula (IV) can beseparated very effectively form the salt of the compound of the formula(I), preferably the hydrochloric acid salt, because the salts of theanilinic side products, in particular the salts of the compound of theformula (IV), preferably the hydrochloric acid salt of the compound ofthe formula (IV), do not precipitate under the conditions according tothe present process and remain in the filtrate. Furthermore in the casewhen the acid is generated in situ by using acylhalogenides thecorresponding acylated derivatives of the anilinic side products, inparticular of the compound of the formula (IV), can be separated easilyfrom the salt of the compound of the formula (I), preferably thehydrochloric acid salt, because the acylated derivatives do notprecipitate under the conditions according to the present process andremain in the filtrate. Therefore the compound of the formula (I), itssalts and its monohydrate can be prepared in a very high purity.

Another embodiment of the present invention is the compound of formula(I), its monohydrate or salt in a very high purity containing orcontaminated with one or more anilinic substances each in an amount ofequal or less than 0.05%, that means from 0.0001% to a maximum of 0.05%,preferably each in an amount of equal or less than 0.025%, that meansfrom 0.0001% to a maximum of 0.025%, most preferably each in an amountof equal or less than 0.01%, that means from 0.0001% to a maximum of0.01% by weight based on the amount of the compound of the formula (I).In other words the another embodiment is a mixture of the compound offormula (I), its monohydrate or salt with one or more anilinicsubstances each anilinic substance in an amount of equal or less than0.05%, that means from 0.0001% to a maximum of 0.05%, preferably each inan amount of equal or less than 0.025%, that means from 0.0001% to amaximum of 0.025%, most preferably each in an amount of equal or lessthan 0.01%, that means from 0.0001% to a maximum of 0.01% by weightbased on the amount of the compound of the formula (I)

Anilinic substances include but are not limited to4-amino-3-fluorophenol, 4-chloro-3-trifluoromethylaniline,4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamide whichis the compound of the formula (IV).

Preference is given to the compound of formula (I), its monohydrate orsalt containing or contaminated with 4-amino-3-fluorophenol and/or4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamide eachin an amount of equal or less than 0.05%, that means from 0.0001% to amaximum of 0.05%, preferably each in an amount of equal or less than0.025%, that means from 0.0001% to a maximum of 0.025%, most preferablyeach in an amount of equal or less than 0.01%, that means from 0.0001%to a maximum of 0.01% by weight based on the amount of the compound ofthe formula (I). In other words preference is given to a mixture of thecompound of formula (I), its monohydrate or salt with4-amino-3-fluorophenol and/or4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamide eachanilinic substance in an amount of equal or less than 0.05%, that meansfrom 0.0001% to a maximum of 0.05%, preferably each in an amount ofequal or less than 0.025%, that means from 0.0001% to a maximum of0.025%, most preferably each in an amount of equal or less than 0.01%,that means from 0.0001% to a maximum of 0.01% by weight based on theamount of the compound of the formula (I).

Preparation of the Compound of the Formula (IV):

The present invention likewise comprises a process for preparing thecompound of the formula (IV) by reacting the compound of the formula(III)

-   -   wherein R¹ and R² are independently selected from the group        consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl,        n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl,        3-pentyl, neopentyl, n-hexyl, 2-hexyl and 3-hexyl,    -   or    -   R¹ and R² are joined and, taken together with the carbon atom to        which they are attached, form a 4- to 7-membered cycloalkyl        ring.        with the compound of the formula (II)

which is 4-chloro-N-methyl-2-pyridinecarboxamide in the presence of abase, followed by adding an acid to deliver the compound of the formula(IV).

In a preferred embodiment of the process for preparing of the compoundof the formula (IV) the compound of the formula (III) is used in asolution of a suitable organic solvent and is formed by reacting4-amino-3-fluorophenol with the compound of the formula (VI)

-   -   wherein R¹ and R² are independently selected from the group        consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl,        n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl,        3-pentyl, neopentyl, n-hexyl, 2-hexyl and 3-hexyl,    -   or    -   R¹ and R² are joined and, taken together with the carbon atom to        which they are attached, form a 4- to 7-membered cycloalkyl        ring.

In a further preferred embodiment of the process for preparing of thecompound of the formula (IV) the compound of the formula (II) is used ina solution of a suitable organic solvent which solution is prepared byneutralization the hydrochloric acid salt of the compound of the formula(II) with a base, preferably with sodium hydroxide, more preferably withan aqueous solution of sodium hydroxide.

In the process for preparing of the compound of the formula (IV)4-amino-3-fluorophenol reacts with the compound of formula (VI) at atemperature of from 20° C. up to reflux temperature, preferably from 50°C. up to reflux temperature, most preferably at the reflux temperatureof the compound of formula (VI) which can be used in excess and assolvent. Optionally a further different solvent can be added such astoluene, ethyl acetate, cyclohexane or a mixture thereof. The volatilereaction components can be removed by azeotropic distillation optionallyunder reduced pressure. The formed compound of the formula (III) can beused in a solution of a suitable organic solvent, preferably in asolution of 1-methyl-2-pyrrolidinone, and is treated with4-chloro-N-methyl-2-pyridinecarboxamide, preferably used in a solutionwith a suitable organic solvent, more preferably in a solution of1-methyl-2-pyrrolidinone, in the presence of a base. The reactionmixture is heated to a temperature of from 50° C. up to 150° C.,preferably from 80° C. up to 120° C. After 1 to 5 h, preferably 2 to 4h, the temperature is adjusted to from 50° C. up to 90° C., preferablyfrom 70° C. up to 90° C., and an acid, preferably acetic acid in water,is added. After cooling, preferably to a temperature of from 0° C. to10° C., and optionally seeding with crystals of the compound of theformula (IV), the compound of the formula (IV) can be isolated byprecipitation.

Preference is given to a compound of the formula (VI) wherein R¹ and R²are independently selected from methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl or R¹ and R² are joined and, takentogether with the carbon atom to which they are attached, form a 4- to7-membered cycloalkyl ring. More preferably the compound of the formula(VI) is selected from the group consisting of 4-methyl-2-pentanone,3-methyl-2-butanone, 2-butanone, 2-pentanone, 4-heptanone,2,4-dimethyl-3-pentanone and cyclohexanone.

Suitable organic solvents in the process for preparing of the compoundof the formula (IV) include but are not limited to1-methyl-2-pyrrolidinone, dimethylformamide, N,N-dimethylacetamid,dimethyl sulfoxide, sulfolane or mixtures of the solvents mentioned.Preferably 1-methyl-2-pyrrolidinone and/or dimethylformamide are used.

In the process for preparing of the compound of the formula (IV)suitable bases are alkali metal hydroxides and alkali metal alkoxides.Preference is given to potassium tert-butoxide. Potassium tert-butoxideis preferably used in a solution, more preferably in a tetrahydrofuransolution.

In order to provide a highly purified version of the compound of theformula (II) it is solved in a suitable organic solvent, treated with anacid which is generated in situ by adding a protic substance and an acidprecursor, precipitated as a salt of the compound of the formula (II),preferably the hydrochloric acid salt of the compound of the formula(II), and neutralized by adding an aqueous solution of a base.

For that purpose the starting compound4-chloro-N-methyl-2-pyridinecarboxamide is solved in a suitable organicsolvent, preferably in toluene, and is treated with an acid which isgenerated in situ by adding a protic substance, for example water and/oran alcohol, preferably an alcohol, and an acid precursor, preferably anacylchloride, for example within 5 to 60 minutes, preferably within 10to 30 minutes, in order to generate the corresponding acid in situ.Preferably the protic substance is added first. The salt of4-chloro-N-methyl-2-pyridinecarboxamide, preferably the hydrochloricacid salt of 4-chloro-N-methyl-2-pyridinecarboxamide, can be isolated byprecipitation. Such purified salt of4-chloro-N-methyl-2-pyridinecarboxamide is solved in a suitable organicsolvent, preferably in toluene, and is neutralized by adding an aqueoussolution of a base, preferably an aqueous solution of sodium hydroxide.After separation of the phases the organic phase is optionallyconcentrated under reduced pressure and a suitable organic solvent,preferably 1-methyl-2-pyrrolidinone, is added to prepare a solutionwhich can be used directly for the preparation of the compound of theformula (IV) as described above.

Suitable organic solvents in the process for preparing of4-chloro-N-methyl-2-pyridinecarboxamide include but are not limited totetrahydrofuran, toluene, ethyl acetate, dioxane, methyl tert-butylether, dimethoxyethane, dimethylsulfoxid, dimethylformamid,1-methyl-2-pyrrolidinone or mixtures of the mentioned solvents. Morepreferably tetrahydofuran, toluene and mixtures thereof are used.

According to the present invention alcohols are organic substancescarrying at least one hydroxyl group. Alcohols include but are notlimited to methanol, ethanol, n-propanol, isopropanol, n-butanol,sec-butanol, isobutanol, n-pentanol, glycerol or a mixture thereof.Preferably methanol, ethanol, isopropnaol are used as alcohols in thepresent process.

In order to prepare the acid in situ suitable precursors include but arenot limited to organic acid halogenides, preferably acylhalegonides suchas acylchlorides and acylbromides, more preferably acetylchloride,acteylbromide, propionylchloride or propionylbromide, most preferablyacetylchloride.

Preference is given to an in situ preparation of the acid without water.

Alternatively the compound of formula (II) and its hydrochloric acidsalt can be prepared as described in WO 05/009961 or in Bankston et al.(Organic Process Research & Development, 2002, 6, 777-781).

The compound of the formula (V) which is4-chloro-3-trifluoromethyl-phenylisocyanate can be prepared as describedin WO 00/42012.

Abbreviations: DCI direct chemical ionization (in MS) DMFdimethylformamide DMSO dimethyl sulfoxide EI electron impact ionization(in MS) ESI electrospray ionization (in MS) h hour(s) min minute(s) m.p.melting point MS mass spectrometry NMR nuclear resonance spectroscopyTHF tetrahydrofuran

WORKING EXAMPLES

¹H-NMR spectra were recorded at room temperature using spectrometersfrom Bruker. Deuterium dimethylsulfoxide was used as solvent includingtetramethylsilan as internal standard (if not otherwised mentioned).

MS spectra were recorded using spectrometers from Waters and AppliedBiosystems. The relative signal intensity is stated (in percent based onthe basis peak).

HPLC was performed using HP 1100 from Hewlett Packard. The definiteconditions are stated with the respective working examples.

Preparation of4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide,its hydrochloride and its monohydrate Stage 14-chloro-N-methyl-pyridine-2-carboxamide hydrochloride

420 g of a solution of 4-chloro-N-methylpyridine-2-carboxamide (preparedaccording to WO2006/034796) in toluene (approx. 30% w/w) and 48.8 g ofethanol were charged into a reaction flask. 67.2 g of acetyl chloridewas added with stirring to such a degree that the temperature of thereaction mixture did not exceed 30° C. After stirring further at roomtemperature for 1.5 h the product was filtered off, washed with toluene(212 g) and dried under reduced pressure (30° C., 80 mbar). In this way156 g (quantitative yield) of 4-chloro-N-methyl-pyridine-2-carboxamidehydrochloride were obtained.

m.p. 173.5-174.5° C.

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm]=2.93 (d, 3H), 7.79-7.97 (m, 1H),8.13-8.26 (m, 1H), 8.71 (d, 1H), 9.03 (br. s., 1H), 13.16 (br. s., 1H).

MS [DCI, NH3]: m/e=171 [M+H]⁺ (M=free base).

HPLC: stationary phase: Nucleodur Gravity C18 (150 mm length, 3 mm ID,3.0 μm particle size); mobile phase A: 1.15 gdi-ammoniumhydrogenphosphate+0.68 mL o-phosphoric acid (85% in water)/1L water; mobile phase B: acetonitrile; UV detection at 254 nm; oventemperature: 45° C., injection volume: 3 μl, flow: 0.5 mL/min.; lineargradient: 5% B→80% B (20 min.), 10 minutes holding time at 80% B;purity: >98% (Rt=17.9 min.).

Stage 2 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide

Method 2a:

A reaction flask with stirrer was charged with 41.4 g of4-chloro-N-methyl-pyridine-2-carboxamide hydrochloride and 100 g oftoluene as solvent. After addition of 68.4 g of water and 19.6 g of anaqueous sodium hydroxide solution (45% w/w) the reaction mixture wasstirred for 30 minutes. The two phases were separated and the aqueouslayer was discarded. The organic layer was concentrated by distillationunder vacuum and toluene was substituted by 1-methyl-2-pyrrolidinone (70g) to yield a solution of 4-chloro-N-methyl-pyridine-2-carboxamide in1-methyl-2-pyrrolidinone.

A second reaction flask with stirrer was charged with 26.7 g of4-amino-3-fluorophenol and 100 g of 4-methyl-2-pentanone. By heating toreflux and additional stirring for 1 hour water was removed byazeotropic distillation. Then the excess 4-methyl-2-pentanone wasremoved by distillation under vacuum and substituted by1-methyl-2-pyrrolidinone (70 g) to prepare a solution containing theimin compound according to formula (III). To the resulting reactionmixture the solution of 4-chloro-N-methyl-pyridine-2-carboxamide in1-methyl-2-pyrrolidinone was added. The reaction mixture was heated toapproximately 100° C. 123.2 g of potassium-t-butoxide in tetrahydrofuran(20% w/w) was added dropwise (within approx. 70 minutes) whilsttetrahydrofuran was removed by distillation. Thereafter the reactionmixture was stirred for additional 3 hours at 100° C. to complete thereaction. After adjusting to 80° C. 350 ml of toluene, of 392 ml waterand 8 g of acetic acid were added. The mixture was stirred for 10minutes at 80° C., cooled down to 50° C. and seeded with crystals of4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide. Aftercooling to 0° C. the suspension was stirred for approximately 30minutes. The product was filtered off, washed with methanol/water (1:3v/v, 144 ml) and dried under reduced pressure (30° C., 80 mbar). In thisway 40.7 g (78% of theory) of4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide were obtainedas brown crystals.

m.p. 140.5-141.2° C.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=2.86 (d, 3H), 5.24-5.35 (s, 2H),6.80-6.86 (m, 1H), 6.89-6.99 (m, 1H), 7.01-7.09 (m, 1H), 7.09-7.15 (m,1H), 7.45 (d, 1H), 8.49 (d, 1H), 8.75-8.85 (m, 1H).

MS [ES]: m/e=262 [M+H]⁺

HPLC: stationary phase: Agilent Zorbax SB-AQ (150 mm length, 3 mm ID,3.5 μm particle size); mobile phase A: 1.40 gdi-potassiumhydrogenphosphat+5.8 ml o-phosphoric acid (8.5% in water)/1L water; mobile phase B: acetonitrile; UV detection at 268 nm; oventemperature: 50° C., injection volume: 3 μl, flow: 0.8 mL/min; lineargradient in two steps: 10% B→37% B (10 min.), 37% B→80% B (10 min.), 10minutes holding time at 80% B; purity: >97% (Rt=9.2 min.).

Method 2b:

A reaction flask with stirrer was charged with 41.4 g of4-chloro-N-methyl-pyridine-2-carboxamide hydrochloride and 100 g oftoluene as solvent. After addition of 68.4 g of water and 19.6 g of anaqueous sodium hydroxide solution (45% w/w) the reaction mixture wasstirred for 30 minutes. The two phases were separated and the aqueouslayer was discarded. The organic layer was concentrated by distillationunder vacuum and toluene was substituted by 1-methyl-2-pyrrolidinone (70g) to yield a solution of 4-chloro-N-methyl-pyridine-2-carboxamide in1-methyl-2-pyrrolidinone.

A second reaction flask with stirrer was charged with 26.7 g of4-amino-3-fluorophenol and 100 g of 3-methyl-2-butanone. By heating toreflux and additional stirring for 3 hours water was removed byazeotropic distillation. Then the excess 3-methyl-2-butanone was removedby distillation under vacuum and substituted by 1-methyl-2-pyrrolidinone(70 g) to prepare a solution containing the imin compound according toformula (III). To the resulting reaction mixture the solution of4-chloro-N-methyl-pyridine-2-carboxamide in 1-methyl-2-pyrrolidinone wasadded. The reaction mixture was heated to approximately 100° C. 123.2 gof potassium-t-butoxide in tetrahydrofuran (20% w/w) was added dropwise(within approx. 3 hours) whilst tetrahydrofuran was removed bydistillation. Thereafter the reaction mixture was stirred for additional2.5 hours at 100° C. to complete the reaction. After adjusting to 80° C.350 ml of toluene of 392 ml water and of 8 g acetic acid were added. Themixture was stirred for 10 minutes at 80° C., cooled down to 50° C. andseeded with crystals of4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide. Aftercooling to 0° C. the suspension was stirred for approximately 30minutes. The product was filtered off, washed with methanol/water (1:3v/v, 144 ml) and dried under reduced pressure (30° C., 80 mbar). In thisway 44.4 g (84% of theory) of4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide were obtainedas light brown crystals.

m.p. 142.2-142.8° C.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=2.83 (d, 3H), 5.27 (s, 2H), 6.78-6.85(m, 1H), 6.86-6.94 (m, 1H), 7.01-7.07 (m, 1H), 7.09-7.14 (m, 1H), 7.41(d, 1H), 8.49 (d, 1H), 8.71-8.87 (m, 1H).

MS [ES]: m/e=262 [M+H]⁺

HPLC: stationary phase: Agilent Zorbax SB-AQ (150 mm length, 3 mm ID,3.5 μm particle size); mobile phase A: 1.40 gdi-potassiumhydrogenphosphat+5.8 ml o-phosphoric acid (8.5% in water)/1L water; mobile phase B: acetonitrile; UV detection at 268 nm; oventemperature: 50° C., injection volume: 3 μl, flow: 0.8 mL/min; lineargradient in two steps: 10% B→37% B (10 min.), 37% B→80% B (10 min.), 10minutes holding time at 80% B; purity: >99% (Rt=9.1 min.).

Method 2c:

A reaction flask with stirrer was charged with 41.4 g of4-chloro-N-methyl-pyridine-2-carboxamide hydrochloride and 100 g oftoluene as solvent. After addition of 68.4 g of water and 19.6 g of anaqueous sodium hydroxide solution (45% w/w) the reaction mixture wasstirred for 30 minutes. The two phases were separated and the aqueouslayer was discarded. The organic layer was concentrated by distillationunder vacuum and toluene was substituted by 1-methyl-2-pyrrolidinone (70g) to yield a solution of 4-chloro-N-methyl-pyridine-2-carboxamide in1-methyl-2-pyrrolidinone.

A second reaction flask with stirrer was charged with 26.7 g of4-amino-3-fluorophenol, 73 g of cyclohexane and 20.6 g of cyclohexanone.By heating to reflux and additional stirring for 3 hours water wasremoved by azeotropic distillation. Then the solvent cyclohexane and theexcess cyclohexanone was removed by distillation under vacuum andsubstituted by 1-methyl-2-pyrrolidinone (70 g) to prepare a solutioncontaining the imin compound according to the formula (III). To theresulting reaction mixture the solution of4-chloro-N-methyl-pyridine-2-carboxamide in 1-methyl-2-pyrrolidinone wasadded. The reaction mixture was heated to approximately 100° C. 126 g ofpotassium-t-butoxide in tetrahydrofuran (20% w/w) was added dropwise(within approx. 40 minutes) whilst tetrahydrofuran was removed bydistillation. Thereafter the reaction mixture was stirred for additional3 hours at 100° C. to complete the reaction. After adjusting to 80° C.350 ml of toluene, of 392 ml water and of 8 g acetic acid were added.The mixture was stirred for 10 minutes at 80° C., cooled down to 50° C.and seeded with crystals of4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide. Aftercooling to 3° C. the suspension was stirred for approximately 30minutes. The product was filtered off, washed with methanol/water (1:3v/v, 144 ml) and dried under reduced pressure (30° C., 80 mbar). In thisway 40.2 g (76% of theory) of4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide were obtainedas light brown crystals.

m.p. 141° C.

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=2.83 (d, 3H), 5.27 (s, 2H), 6.78-6.85(m, 1H), 6.86-6.94 (m, 1H), 7.01-7.07 (m, 1H), 7.09-7.14 (m, 1H), 7.41(d, 1H), 8.49 (d, 1H), 8.71-8.87 (m, 1H).

MS [ES]: m/e=262 [M+H]+

HPLC: stationary phase: Agilent Zorbax SB-AQ (150 mm length, 3 mm ID,3.5 μm particle size); mobile phase A: 1.40 gdi-potassiumhydrogenphosphat+5.8 ml o-phosphoric acid (8.5% in water)/1L water; mobile phase B: acetonitrile; UV detection at 268 nm; oventemperature: 50° C., injection volume: 3 μl, flow: 0.8 mL/min; lineargradient in two steps: 10% B→37% B (10 min.), 37% B→80% B (10 min.), 10minutes holding time at 80% B; purity: >98% (Rt=9.1 min.).

Stage 34-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamidemonohydrate

A reaction flask with stirrer was charged with 20.0 g of4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide and 180 g oftetrahydrofuran as solvent. A solution of 18.7 g of4-chloro-3-trifluoromethyl-phenylisocyanate and 21.1 g of toluene wasadded dropwise within approximately 90 minutes at room temperature. Theresulting solution was stirred for 3 hours to complete the reaction.After then 30 g of tetrahydrofuran and 7.8 g of methanol were added tothe reaction mixture. Following 9.0 g of acetyl chloride were addeddropwise within 15 minutes to the reaction mixture. After additionalstirring for approximately 2 hours the suspension was filtered and thesolid was washed with tetrahydofuran (18.2 g) and acetone (136.4 g). Thesolid was added to a mixture of acetone (268.6 g), water (55.8 g) and anaqueous sodium hydroxide solution (8.2 g, 45% w/w) at 40° C. The mixturewas stirred for additional 30 minutes. Then the crystallization wasinitiated by seeding with crystals of4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamidemonohydrate. After cooling to 20° C. 31.6 g of water were added. Thesuspension was cooled down to approx. 3° C. and stirred for 30 minutes.The product was filtered off, washed with a cold mixture of acetone (106g) and water (44 g) and dried under reduced pressure (30° C., 80 mbar).In this way 31.8 g (83% of theory) of4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamidemonohydrate were obtained as white crystals.

1H-NMR (500 MHz, METHANOL-d4): δ [ppm]=2.94 (s, 3H), 6.96-7.01 (m, 1H),7.05-7.11 (m, 2H), 7.49-7.53 (m, 1H), 7.56-7.59 (m, 1H), 7.61-7.65 (m,1H), 8.00-8.03 (m, 1H), 8.15-8.20 (m, 1H), 8.46-8.51 (m, 1H).

MS [ES]: m/e=483 [M+H]⁺

HPLC: stationary phase: Eclipse XDB-C8 (150 mm length, 2.1 mm ID, 3.5 μmparticle size); mobile phase A: 1.0 g hexane-1-sulfonic acid sodiumsalt+1.0 mL trifluoro acetic acid/1 L water; mobile phase B:acetonitrile; UV detection at 232 nm; oven temperature: 43° C.,injection volume: 3 μl, flow: 0.5 mL/min; linear gradient in 3 steps: 5%B→36% B (14.5 min.), 36% B→44% B (6 min.), 44% B→80% B (9.5 min.), 10minutes holding time at 80% B; purity: >99.5% (Rt=25.7 min.), relevantpotential by-products: 4-amino-3-fluorophenol at RRT (relative retentiontime) of 0.10: typically <0.01% (2.6 min.),4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide RRT 0.37:typically <0.01% (9.5 min.); RRT 0.46(4-(3-Fluoro-4-{[2-(methylcarbamoyl)pyridin-4-yl]amino}phenoxy)-N-methylpyridine-2-carboxamide):typically <0.15% (11.7 min.); RRT 0.69(4-(3-fluoro-4-{[(2-fluoro-4-{[2-(methylcarbamoyl)pyridin-4-yl]oxy}phenyl)carbamoyl]ami

no}phenoxy)-N-methylpyridine-2-carboxamide): typically <0.15% (17.7min.).

HPLC (trace analysis method for quantification of4-amino-3-fluorophenol): stationary phase: X-Bridge Shield C18 (150 mmlength, 3.0 mm ID, 3.5 μm particle size); mobile phase A: 1.5 gpotassium dihydrogenphosphate+0.5 g dipotassium hydrogenphosphate 1 Lwater; mobile phase B: acetonitrile; UV detection at 228 nm; oventemperature: 50° C., injection volume: 3 μl, flow: 1.0 mL/min; 5 minutesholding time at 5% B, linear gradient in 1 step: 5% B→80% B (10 min.),RT of 4-amino-3-fluorophenol: 1.7 min., quantification against externalstandard of 4-amino-3-fluorophenol.

HPLC (trace analysis method for quantification of4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide): stationaryphase: X-Bridge Shield C18 (150 mm length, 3.0 mm ID, 3.5 μm particlesize); mobile phase A: 1.5 g potassium dihydrogenphosphate+0.5 gdipotassium hydrogenphosphate 1 L water; mobile phase B: acetonitrile;UV detection at 228 nm; oven temperature: 50° C., injection volume: 3μl, flow: 1.0 mL/min; linear gradient in 1 step: 8% B→80% B (15 min.),RT of 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide: 7.0min., quantification against external standard of4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide.

Stage 44-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide

10.2 g of4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamidemonohydrate was dried under reduced pressure (21 mbar) at 90° C. for 3hours. In this way 9.8 g of4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)-amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamidewere obtained as white crystals.

m.p. 187-188° C.

¹H-NMR (400 MHz, METHANOL-d₄): δ [ppm]=2.94 (s, 3H), 6.94-7.13 (m, 3H),7.51 (d, 1H), 7.58 (d, 1H), 7.61-7.67 (m, 1H), 8.01 (d, 1H), 8.17 (t,1H), 8.45-8.53 (m, 1H).

MS [ES]: m/e=483 [M+H]⁺

HPLC: stationary phase: Eclipse XDB-C8 (150 mm length, 2.1 mm ID, 3.5 μmparticle size); mobile phase A: 1.0 g hexane-1-sulfonic acid sodiumsalt+1.0 mL trifluoro acetic acid/1 L water; mobile phase B:acetonitrile; UV detection at 232 nm; oven temperature: 43° C.,injection volume: 3 μl, flow: 0.5 mL/min; linear gradient in 3 steps: 5%B→36% B (14.5 min.), 36% B→44% B (6 min.), 44% B→80% B (9.5 min.), 10minutes holding time at 80% B; purity: >99.5% (Rt=25.2 min.), relevantpotential by-products: 4-amino-3-fluorophenol at RRT (relative retentiontime) of 0.10: typically <0.01% (2.5 min.),4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide RRT 0.36:typically <0.01% (9.1 min.); RRT 0.46(4-(3-Fluoro-4-{[2-(methylcarbamoyl)pyridin-4-yl]amino}phenoxy)-N-methylpyridine-2-carboxamide):typically <0.15% (11.3 min.); RRT 0.69(4-(3-fluoro-4-{[(2-fluoro-4-{[2-(methylcarbamoyl)pyridin-4-yl]oxy}phenyl)carbamoyl]ami

no}phenoxy)-N-methylpyridine-2-carboxamide): typically <0.15% (17.2min.).

HPLC (trace analysis method for quantification of4-amino-3-fluorophenol): stationary phase: X-Bridge Shield C18 (150 mmlength, 3.0 mm ID, 3.5 μm particle size); mobile phase A: 1.5 gpotassium dihydrogenphosphate+0.5 g dipotassium hydrogenphosphate 1 Lwater; mobile phase B: acetonitrile; UV detection at 228 nm; oventemperature: 50° C., injection volume: 3 μl, flow: 1.0 mL/min; 5 minutesholding time at 5% B, linear gradient in 1 step: 5% B→80% B (10 min.),RT of 4-amino-3-fluorophenol: 1.7 min., quantification against externalstandard of 4-amino-3-fluorophenol.

HPLC (trace analysis method for quantification of4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide): stationaryphase: X-Bridge Shield C18 (150 mm length, 3.0 mm ID, 3.5 μm particlesize); mobile phase A: 1.5 g potassium dihydrogenphosphate+0.5 gdipotassium hydrogenphosphate 1 L water; mobile phase B: acetonitrile;UV detection at 228 nm; oven temperature: 50° C., injection volume: 3μl, flow: 1.0 mL/min; linear gradient in 1 step: 8% B→80% B (15 min.),RT of 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide: 7.0min., quantification against external standard of4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide.

What is claimed is:
 1. A process for preparing the compound of theformula (I)

or its monohydrate by treating the compound of the formula (IV)

with the compound of formula (V)

in a reaction mixture and thereafter the dissolved compound of theformula (I) in solution is treated with an acid to form a salt of thecompound of the formula (I) which precipitates from the solutioncontaining the dissolved compound of the formula (I), and said salt ofthe compound of the formula (I) is then treated with an aqueous basicsolution to precipitate the monohydrate of the compound of the formula(I), optionally said monohydrate is dried under reduced pressure untilthe compound of the formula (I) is formed.
 2. The process of claim 1wherein the monohydrate of the compound of the formula (I) precipitatesat a temperature of from 35° C. to 45° C.
 3. The process of claim 1 forpreparing of the compound of the formula (I) wherein the monohydrate isdried under reduced pressure until the compound of the formula (I) isformed.
 4. The process of claim 1 wherein the acid is generated in situin the reaction mixture after the compound of the formula (I) is formedby adding to the reaction mixture a protic substance and an acidprecursor.
 5. The process of claim 4 wherein the acid is generated insitu in the reaction mixture after the compound of the formula (I) isformed by adding to the reaction mixture an alcohol and an acylchloride.6. The process of claim 5 wherein the alcohol is ethanol and theacylchloride is acetylchloride.
 7. The process of claim 1 wherein thecompound of the formula (IV) is prepared by reacting the compound of theformula (III)

wherein R¹ and R² are independently selected from the group consistingof hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl,2-hexyl and 3-hexyl, or R¹ and R² are joined and, taken together withthe carbon atom to which they are attached, form a 4- to 7-memberedcycloalkyl ring, with the compound of the formula (II)

in the presence of a base, followed by adding an acid to deliver thecompound of the formula (IV).
 8. The process of claim 7 wherein thecompound of the formula (III) is used in a solution of a suitableorganic solvent and is formed by reacting 4-amino-3-fluorophenol withthe compound of the formula (VI)

wherein R¹ and R² are independently selected from the group consistingof hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl,2-hexyl and 3-hexyl, or R¹ and R² are joined and, taken together withthe carbon atom to which they are attached, form a 4- to 7-memberedcycloalkyl ring.
 9. The process of claim 7 wherein the compound of theformula (II) is used in a solution of a suitable organic solvent whichsolution is prepared by neutralization the hydrochloric acid salt of thecompound of the formula (II) with a base.
 10. The process of claim 7wherein the compound of the formula (II) is dissolved in a suitableorganic solvent, treated with an acid which is generated in situ byadding a protic substance and an acid precursor, precipitated as a saltof the compound of the formula (II), and neutralized by adding anaqueous solution of a base.
 11. The process of claim 10 wherein theprotic substance is an alcohol and the acid precursor is anacylchloride.